Process for the preparation of aryl hydrazone and aryl hydrazine

ABSTRACT

A process for the preparation of a compound of formula (I): 
                         
wherein Ar represents an optionally substituted aromatic carbocycle or heterocycle, and R 1  and R 2  independently represent hydrogen, C 1-10  alkyl, C(O)C 1-10  alkyl or optionally substituted aryl provided that R 1  and R 2  are not both hydrogen which process comprises reacting together a compound of formula (II):
 Ar—X  (II) 
wherein Ar is as defined in relation to formula (I) and X represents a leaving group with a a compound of formula (III)
 
                         
wherein R 1  and R 2  are as defined in relation to formula (I) under aqueous conditions in the presence of a Pd (II) salt, a ligand and a Group I or Group II metal hydroxide base at a pH greater than 7. Compounds of formula (I) may be hydrolysed to the corresponding hydrazine.

This application is a 371 of PCT/GB02/04459 filed Aug. 2, 2002.

The present invention relates to a process for the preparation of arylhydrazones and their use in making aryl hydrazines.

Aryl hydrazines are used widely as intermediates in agrochemical andpharmaceutical synthetic processes, particularly in the synthesis ofcompounds having heterocyclic rings.

In J. Am. Chem. Soc., (1998) 120, 6621–2 there is described thepalladium-catalysed preparation of hydrazines under anhydrous conditionsusing bases that are incompatible with water. The use of suchnon-aqueous conditions results in a process that is expensive and makeseffluent with a high chemical oxygen demand (COD). These factors makethe process undesirable for large-scale manufacture of hydrazines.

According to the present invention there is provided a process for thepreparation of a compound of formula (I):

wherein Ar represents an optionally substituted aromatic carbocycle orheterocycle, and R¹ and R² independently represent hydrogen, C₁₋₁₀alkyl, C(O)C₁₋₁₀ alkyl or optionally substituted aryl provided that R¹and R² are not both hydrogen which process comprises reacting together acompound of formula (II):Ar—X  (II)wherein Ar is as defined in relation to formula (I) and X represents aleaving group with a compound of formula (III)

wherein R¹ and R² are as defined in relation to formula (I) underaqueous conditions in the presence of a Pd (II) salt, a ligand and aGroup I or Group II metal hydroxide base at a pH greater than 7.

The expression “alkyl” refers to fully saturated straight or branchedhydrocarbon chains having from one to ten, preferably one to six carbonatoms. Examples include methyl, ethyl, n-propyl, iso-propyl, n-butyl,t-butyl and n-hexyl. Expressions such as “alkoxy” and “haloalkyl” shouldbe construed accordingly.

As used herein, the term “halogen” includes fluorine, chlorine, bromineand iodine.

Haloalkyl groups are alkyl groups which are substituted with one or moreof the same or different halogen atoms and are, for example, CF₃, CF₂Cl,CH₂CF₃, CH₂CH₂CF₃, CH₂(CF₂)₂CH₃,CH₂CHF₂ or CH₂CF₂CF₂CF₃.

The reaction is preferably performed in the absence of air.

The reaction occurs in the aqueous phase but optionally an organicsolvent may be added. Suitable organic solvents are hydrocarbons such asaromatic carbocycles for example methyl substituted benzenes, etherssuch as tetrahydrofuran or alcohols such as methanol, ethanol andoctanol.

Preferred organic solvents are aromatic carbocyclic hydrocarbons such asmethyl substituted benzenes. A particularly useful organic solvent istoluene or xylene.

The compounds of formula (I) may be hydrolysed to aryl hydrazinecompounds of formula (IV)

wherein Ar, R¹ and R² are as defined in relation to formula (I). Thehydrolysis is a standard organic transformation which can be performedby many methods such as hydrolysis with acids for example mineral acids.Suitable processes and conditions are those described in D E Bergbreiter& M Momongen, “Comprehensive Organic Synthesis” (1991), 2, 523–524 andin E. Enders, Houben-Weyl “Methoden der Organischen Chemie”, StickstoffVerbindungen I, 10/2 (1967), p310–312.

The process of the invention enables preparation of aryl hydrazones andaryl hydrazines using simple, inexpensive inorganic bases, under aqueousconditions, and is a relatively inexpensive process compared with thatdescribed in the prior art process which uses an expensive base(potassium t-butoxide) and which necessitates anhydrous conditions.

The reaction is applicable to a wide range of carbocyclic aryl groups.Typical aromatic carbocycle groups Ar and aryl groups R¹ and R² are ringsystems that may be mono-, bi- or tricyclic. Examples of such ringsinclude phenyl, naphthalenyl, anthracenyl or phenanthrenyl, preferablyphenyl.

Typical aromatic heterocycle groups Ar are aromatic ring systemscontaining at least one heteroatom and consisting either of a singlering or of two or more fused rings. Preferably, single rings willcontain up to three and bicyclic systems up to four heteroatoms whichwill preferably be chosen from nitrogen, oxygen and sulphur. Examples ofsuch groups include furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl,1,2,3-triazolyl, 1,2,4-triazolyl, oxazolyl, isoxazolyl, thiazolyl,isothiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl,1,2,5-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, pyridyl, pyrimidinyl,pyridazinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl,1,3,5-triazinyl, benzofuryl, benzisofuryl, benzothienyl, benzisothienyl,indolyl, isoindolyl, indazolyl, benzothiazolyl, benzisothiazolyl,benzoxazolyl, benzisoxazolyl, benzimidazolyl, quinolinyl, isoquinolinyl,cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl,benzotriazinyl, purinyl, pteridinyl and indolizinyl. Preferred examplesof heteroaromatic radicals include pyridyl, pyrimidyl, triazinyl,thienyl, furyl, oxazolyl, isoxazolyl, and thiazolyl.

A preferred ring for Ar is phenyl.

When the groups R¹, R² and Ar are substituted, the substituents are oneor more groups independently selected from alkyl, halogen, cyano, nitro,haloalkyl, amino, acylamino, HO₂C, C₁₋₆ alkoxy (itself optionallysubstituted by C₁₋₆ alkoxy), aryl(C₁₋₄)alkoxy, C₁₋₆alkylcarbonyl,C₁₋₆alkoxycarbonyl, C₁₋₆alkylaminocarbonyl, di(C₁₋₆ alkyl)aminocarbonyl,phenyl, halophenyl, C₁₋₆ alkylphenyl, C₁₋₆alkoxycarbonyl-phenyl, C₁₋₆alkoxyphenyl, heteroaryl, aryloxy, arylcarbonyloxy, heteroaryloxy,heterocyclyl, heterocyclyloxy, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyloxy, C₅₋₇cycloalkenyl and phosphonato groups where aryl and herteroaryl have themeanings as defined for Ar and heterocyclyl means a non-aromatic ringsystem containing at least one heteroatom and consisting either of asingle ring or of two or more fused rings such as pyrrolidine,piperidine, thiomorpholine and morpholine each of which may besubstituted by one or two independently selected (C₁₋₆) alkyl groups.Where a group has more than one substituent the substituents may be thesame or different.

Preferred substituents for R¹, R² and Ar include C₁₋₈ alkyl, halogen,cyano, nitro, C₁₋₈haloalkyl, acylamino, and C₁₋₆ alkoxy (itselfoptionally substituted by C₁₋₆ alkoxy).

More preferred substituents for R¹, R² and Ar include C₁₋₆ alkyl,halogen, nitro, trifluoromethyl and C₁₋₆ alkoxy.

Preferably R¹ and R² are independently C₁₋₈ alkyl, phenyl or phenylsubstituted by one or more of C₁₋₈ alkyl, halogen, cyano, nitro, C₁₋₈haloalkyl, acylamino, and C₁₋₆ alkoxy (itself optionally substituted byC₁₋₆ alkoxy).

More preferably R¹ and R² are independently C₁₋₆ alkyl, phenyl or phenylsubstituted by one or more of C₁₋₆ alkyl, halogen, nitro,trifluoromethyl or C₁₋₆ alkoxy.

Preferably Ar is phenyl or phenyl substituted by one or more of C₁₋₈alkyl, halogen, cyano, nitro, C₁₋₈haloalkyl, acylamino, and C₁₋₆ alkoxy(itself optionally substituted by C₁₋₆alkoxy).

More preferably Ar is phenyl or phenyl substituted by one or more ofC₁₋₆ alkyl, halogen, nitro, trifluoromethyl or C₁₋₆ alkoxy.

A preferred leaving group X is I, Br, Cl, —O-triflate or O-tosylate.

Suitable compounds that may be prepared by the invention include3-trifluoromethyl-phenyl hydrazine, 4-methoxy-phenyl hydrazine,4-nitro-phenyl hydrazine and 4-chloro-phenyl hydrazine.

Preferably, the base is sodium, potassium or lithium hydroxide or ahydroxide or oxide of magnesium, calcium or caesium.

The Pd (II) salt catalyst is preferably palladium chloride or palladiumacetate.

Preferably the ligand is 2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl(BINAP) either as a racemate or as(S)-(−)-2,2′-Bis(diphenylphosphino)-1,1-binaphthyl). The function of theligand is to generate the catalytic species.

The reaction is preferably performed at a temperature of from 50° C. to150° C.

More preferably the temperature is from 70° C. to 130° C., even morepreferably 80° C. to 100° C.

The reaction may be operated at atmospheric pressure or at elevatedpressure.

The ratio of compounds of formula (II to formula (III) is preferablyfrom 3:1 to 1:3, more preferably 1.5:1 to 1:1.5, more preferably 1:1.

Preferably, the pH is greater than 9, more preferably greater than 10.

The invention will now be illustrated by way of example only. All partsand percentages are by weight unless otherwise stated.

EXAMPLE 1

This Example Illustrates the Preparation ofN-(3-benzotriflouro)-benzophenone Hydrazone

Materials Weight 100% Wt Gram Molar MATERIAL MWt Grams Grams Mole Ratio3-bromobenzotrifluoride 225 2.49 2.47 0.011 1.0 Benzophenone hydrazone196 2.25 2.16 0.011 1.0 (S)-(−)-BINAP 622.7 0.128 0.124 0.0002 0.018Palladium acetate 224.5 0.034 0.034 0.00025 0.023 Toluene (degassed) 9215 mls 13.0 0.141 12.84 1.0 Molar NaOH 40 15 ml  0.6 0.015 1.36

Toluene (15 mls; 13.0 gm) degassed with helium was charged to a drynitrogen purged flask fitted with a nitrogen bubbler, stirrer andthermometer and the stirrer started. Palladium acetate (0.034 gms) andBINAP (0.124 gm) were added rapidly and stirred in to give a yellowsolution. 3-Bromobenzotrifluoride (2.47 gm) was then added at ambienttemperature and after stirring for 5 minutes benzophenone hydrazone(2.16 gm) was charged to the yellow solution causing it to turn to adark red colour. Molar sodium hydroxide solution (15 mls.) degassed withhelium was added and the resulting mixture heated to reflux (85–90° C.)over 20 minutes. The two-phase mixture was stirred at reflux for a totalof about 8 hours by which time GC analysis showed that the reaction wascomplete. The reaction mixture was cooled to ambient temperature,transferred to a separating funnel and the lower aqueous phase separatedoff. The toluene layer was washed with water (10 mls) and evaporatedunder reduced pressure on a rotary evaporator to give the requiredhydrazone as a crude light brown viscous oil residue.

-   -   Weight of crude product=3.72 gm.    -   Strength (GC area %)=87.8%    -   Yield (based on GC Area % strength)=87.3%

EXAMPLE 2

This Example Illustrates the Preparation ofN-(3-benzotriflouro)-benzophenone Hydrazone

Act. wt. Str. % 100% mol Material g w/w wt. g MW g moles ratio3-bromobenzotrifluoride 2.49 99 2.47 225 0.0110 1.00 Benzophenonehydrazone 2.25 98 2.21 196 0.0113 1.03 Palladium acetate 0.0351 980.0344 224.5 1.53 × 10⁻⁴ 0.0140 Racemic-BINAP 0.1307 98 0.128 622 2.06 ×10⁻⁴ 0.0188 Sodium hydroxide sol^(n) 15 ml  1.01 N 40 0.01515 1.38Toluene 15 ml 99.95

The palladium acetate, BINAP and toluene (previously degassed withhelium) were charged to the reactor in a nitrogen atmosphere and themixture was stirred for 10 minutes. The 3-bromobenzotrifluoride andbenzophenone hydrazone were charged to the reactor. The aqueous sodiumhydroxide solution (previously degassed with helium) was added and themixture was heated to 90° C. and stirred at that temperature for 7.25hours. The reaction mixture was cooled to room temperature and allowedto stand overnight. The reaction was continued the next day by heatingto 90° C. After a further 7 hours, the mixture was cooled, 15 ml waterwas added to dissolve precipitated solid and the two phases wereseparated. The toluene phase was washed with water (15 ml) and thesolvent was removed at 40° C. and reduced pressure on a rotaryevaporator. The yield of product was 93%.

The experiment was repeated with 4-nitrobromobenzene,4-methoxybromobenzene and 4-chlorobromobenzene using the same procedureas for 3-bromobenzotrifluoride.

The yield of hydrazone is shown below:

Arylbromide Yield of Hydrazone 3-bromobenzotrifluoride 934-nitrobromobenzene 94 4-methoxybromobenzene 2 4-chlorobromobenzene 55

1. A process for the preparation of a compound of formula (I):

wherein Ar represents an optionally substituted aromatic carbocycle orheterocycle, and R¹ and R² independently represent hydrogen, C₁₋₁₀alkyl, C(O)C₁₋₁₀ alkyl or optionally substituted aryl provided that R¹and R² are not both hydrogen which process comprises reacting together acompound of formula (II):Ar—X  (II) wherein Ar is as defined in relation to formula (I) and Xrepresents a leaving group with a compound of formula (III)

wherein R¹ and R² are as defined in relation to formula (I) underaqueous conditions in the presence of a Pd (II) salt, a ligand and aGroup I or Group II metal hydroxide base at a pH greater than
 7. 2. Aprocess according to claim 1 which comprises the further step ofhydrolysing a compound of formula (I) as defined in the claim to acompound of formula IV

wherein Ar, R¹ and R² are as defined in relation to formula (I).
 3. Aprocess according to claim 1 or claim 2 wherein Ar is optionallysubstituted phenyl.
 4. A process according to claim 1 or claim 2 whereinR¹ and R² are independently C₁₋₈ alkyl, phenyl or phenyl substituted byone or more of C₁₋₈ alkyl, halogen, cyano, nitro, C₁₋₈ haloalkyl,acylamino, and C₁₋₆ alkoxy (itself optionally substituted by C₁₋₆alkoxy).
 5. A process according to claim 1 or claim 2 wherein thecatalyst is palladium chloride or palladium acetate.
 6. A processaccording to claim 1 or claim 2 wherein the ligand is2,2′-bis(diphenylphosphino)-1,1′-binaphthyl or(S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl).
 7. A processaccording to claim 1 or claim 2 wherein the base is sodium, potassium orlithium hydroxide or a hydroxide or oxide of magnesium, calcium orcaesium.
 8. A process according to claim 1 or claim 2 wherein the pH isgreater than 9.